Childhood and adolescent obesity is a significant health problem in the United States. Its prevalence has increased 10 fold in the last 20 years. Almost 15% of children between 2 and 18 years old are now overweight (BMI >95th percentile for age and gender). The increasing trend of obesity places a significant health and economic burden in our society. Mechanisms governing obesity are complex and not fully elucidated. Obesity involves a complex interaction among a myriad of environmental and genetic factors. The hypothalamus in the brain is critical to the regulation and maintenance of food intake and energy balance. Within the hypothalamus, a key center for satiety is the ventromedial hypothalamic nucleus (VMH). When VMH is destroyed in rodent species, they become hyperphagic and obese. Understanding the molecular mechanisms of VMH function is critical to the study of obesity;however, research in the VMH has been impeded by a lack of definitive VMH markers. To date, steroidogenic factor (sf-1) is the only specific marker for VMH neurons and is critical for the terminal differentiation of VMH neurons. Our laboratory has identified a list of novel VMH-enriched genes with the use of gene profiling and microarray analysis. The overall goal of my research proposal is to understand the biology of the VMH in energy homeostasis. The approach is to study the function of novel VMH-enriched genes. The specific aims are first, to study the development of the VMH by evaluating the role of a novel transcription factor, forebrain embryonic zinc-finger (fez), and its interaction with sf-1;second, to study the excitatory function of the VMH by examining the role of vesicular glutamate transporter 2 (VGLUT2) and its impact on food intake and body weight when it is selectively removed from the VMH;and third, to examine the adaptive and epigenetic function of the VMH by identifying genes that are differentially expressed in pups born to females that are undernourished or overnourished during pregnancy. The studies will be performed with stable cell lines and mice of normal, transgenic, and conditional knockout background. The research techniques used to accomplish these projects will include standard molecular biology and genetics techniques, including cell culture, in situ hybridization and immunocytochemistry, transgenic technologies, and microarray analysis. This research will facilitate my training as an independent physician scientist as well as identifying potential therapeutic and preventative approaches in managing childhood obesity. Understanding the function and mechanism of the VMH will help us to understand how the hypothalamus controls certain nutritional disorders, such as obesity, and type II diabetes, as well as other complex human behaviors, ranging from anorexia nervosa to gender dysphoria.